Interleukin-1β Induces an Early Decrease in Insulin Release, (Pro)Insulin Biosynthesis and Insulin Mrna in Mouse Pancreatic Islets by a Mechanism Dependent on Gene Transcription and Protein Synthesis

Abstract

In an attempt to further characterize the mechanisms of action of recombinant interleukin-1β(rIL-1β) on mouse pancreatic islets, islets were exposed for different periods of time (6,12 and 24 h) to 50 U/ml rIL-1β. After 6 h there was already a significant decrease in glucose(16.7 mM)-induced insulin release. This was followed at 12 h by a decrease in insulin mRNA contents and (pro)insulin biosynthesis and, after 24 h, by a decrease in islet insulin contents. There was no decrease in total protein biosynthesis or DNA contents in any of the studied time points and the glucose oxidation rates were not affected by rIL-1β after 12 h of exposure. A similar inhibition of insulin release, (pro)insulin biosynthesis and insulin mRNA content was observed 12 h after a short (2 h) exposure of the islets to rIL-β, suggesting that a brief exposure of mouse islets to the cytokine can modify their function for several hours. When islets were exposed for 12 h to 50 U/ml rIL-1β in the presence of either an inhibitor of gene transcription (actinomycin D) or an inhibitor of mRNA translation (cycloheximide) there was a complete protection against the suppressive effects of rIL-1βon insulin release, (pro)insulin biosynthesis and insulin mRNA contents. However, when islets were exposed for 2 h to rIL-1βin the presence of aclinomycin D, and studied 12 h later, actinomycin counteracted the inhibitory effects of rIL-1βon insulin release, but not on (pro)insulin biosynthesis. The data indicate that rIL-1β induces an early inhibition of glucose-induced insulin release, which precedes the decrease in insulin mRNA content and (pro)insulin biosynthesis, suggesting that a decrease in insulin synthesis can not explain the observed decrease in insulin release. Both effects of rIL-1β are related to gene transcription and protein biosynthesis, and are independent of an impairment in glucose metabolism. It is conceivable that the protein(s) induced by rIL-1β are related to insulin mRNA degradation.